The present invention relates to a novel N-acetylneuraminic acid derivative and a process for the preparation thereof. More particularly, it relates to a novel N-acetylneuraminic acid derivative which has utility as a medicine which remarkedly inhibits the metastasis of cancer cells, and a process for preparing the same.
It has been known in the art that N-acetylneuraminic acid, which is referred to as sialic acid, occupies the glycoside terminals of a composite glycoside, such as glycolipid and glycoprotein, present at cell surfaces to provide important effects on the differentiation, maturity, functions and intercellular actions of organic cells. A variety of N-acetylneuraminic acid derivatives has been synthesized and subjected to research work.
Such prior art references are, for example, as follows:
R. Kuhn, P. Lutz und D. L. MacDonald, Chem Ber., 99 611-617 (1966), Synthese anomerer Sialinsaure-methylketoside.
P. Meindl und H. Tuppy, Mh. Chem., 100 1295-1306 (1969), Uber 2-Deoxy-2,3-dehydro-sialinsauren, I. Mitt.: Synthese und Eigenschaften von 2-Deoxy-2,3-dehydro-N-acylneuraminsauren und deren Methylestern.
R. Brossmer, H. Friebolin, G. Keilich, B. Loser and M. Supp, Hopp-Seyler's Z. physiol. Chem., 359 1064 (1978) Synthesis of Disaccharides Containing N-Acetyl-D-neuraminic Acid.
M. N. Sharma and R. Eby, Carbohydr. Res., 127 201-210 (1984), Synthesis and Conformational Studies of 2-.beta.-Chloro,2-.alpha..Fluoro, and 2-.beta.-Fluoro-Derivatives of 2-Deoxy-N-acetylneuraminic acid.
L. Holmquist and R. Brossmer, Hoppe-Seyler's Z. Physiol, Chem., 353 1346-1350 (1972), Synthesis and Properties of the 2-Aminoethyl .alpha.- and the 2-Pyridyl .alpha.- and .beta.-Ketosides of N-Acetyl-D-neuraminic Acid.
L. Holmquist and R. Brossmer, FEBS Letters, 22 46-48 (1972), ON THE SPECIFICITY OF NEURAMINIDASE: The carboxymethyl .alpha.-ketoside of N-acetyl-D-neuraminic acid, a Vibrio cholerae neuraminidase substrate having two anionic sites.
T. Ogawa and M. Sugimoto, Carbohydr. Res., 128 C1-C4 (1984), Synthesis of .alpha.- and .beta.-(2-9)-linked disialylglycerolipids.
H. Paulsen and H. Tietz, Carbohydr. Res., 125 47-64 (1984), Synthese eines trisaccharides aus N-acetylneuraminsaure and N-acetyllactosamin.
We have previously found that the N-acetylneuraminic acid derivative having a nucleoside or glucose coupled to the N-acetylneuraminic acid through .alpha.-bonding has excellent physiological activities, and have already filed a patent application relating to such a derivative and the process for preparing the same based on that finding (Japanese patent application No. 77672/1981; corresponding U.S. patent application which has matured to United Pat. No. 4,447,600).
We have now found that a novel N-acetylneuraminic acid derivative, in addition to the previously found derivative, in which the nucleoside is coupled through .beta.-bonding to the N-acetylneuraminic acid can be isolated and purified by applying unique dual-chromatography in the aforementioned known process. Furthermore, we were surprised to find that the novel derivative isolated and purified as aforementioned has a pronounced and unique pharmaceutical efficacy as regards inhibition of metastatis of cancer cells. The present invention has been accomplished on the basis of this finding.